Ultrasonic waves improves the tumoricidal effect of 5-flurouracil loaded on polymeric nanoparticles in chemically induced hepatocellular carcinoma in mice (original) (raw)
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Disposition of Ultrasound Sensitive Polymeric Drug Carrier in a Rat Hepatocellular Carcinoma Model
Academic Radiology, 2011
Rational and Objectives-A doxorubicin-loaded microbubble has been developed that can be destroyed with focused ultrasound resulting in fragments, or "nanoshards" capable of escaping through the leaky tumor vasculature, promoting accumulation within the interstitium. This study utilizes a rat liver cancer model to examine the biodistribution and tumoral delivery of this microbubble platform compared with de novo drug-loaded polymer nanoparticles and free doxorubicin. Methods-Microbubbles (1.8µm) and 217nm nanoparticles were prepared containing 14-C labeled doxorubicin. Microbubbles, nanoparticles, a combination of the two, or free doxorubicin were administered intravenously in rats bearing hepatomas, concomitant with tumor insonation. Doxorubicin levels in plasma, organs and tumors were quantified after 4hours, 7 and 14days. Tumors were measured upon sacrifice and evaluated with autoradiography and histology. Results-Animals treated with microbubbles had significantly lower plasma doxorubicin concentrations (0.466±0.068%/ml) compared with free doxorubicin (3.033±0.612%/ml, p=0.0019). Drug levels in the myocardium were significantly lower in animals treated with microbubbles compared to free doxorubicin (0.168%/g tissue vs. 0.320%/g, p=0.0088). Tumors treated with microbubbles showed significantly higher drug levels than tumors treated with free doxorubicin (2.491±0.501 %/g vs. 0.373±0.087 %/g, p=0.0472). These tumors showed significantly less growth than tumors treated with free doxorubicin (p=0.0390). Conclusions-Doxorubicin loaded microbubbles triggered with ultrasound provided enhanced, sustained drug delivery to tumors, reduced plasma and myocardium doxorubicin levels and arresting tumor growth. The results offer superior treatment than injection of de novo synthesized nanoparticles.
Ultrasound Activated Nano-Encapsulated Targeted Drug Delivery and Tumour Cell Poration
Advances in Experimental Medicine and Biology, 2011
Introduction : Recently, ultrasonic drug release has been a focus of many research groups for stimuli responsive drug release. It has been demonstrated that a focused ultrasound (FUS) beam rapidly increases the temperature at the focused tissue area. One potential mechanism of drug targeting is to utilize the induced heat to release or increase penetration of chemotherapy to cancer cells. The efficiency of targeted drug delivery may increase by using FUS beam in conjugation with nanoencapsulated drug carriers.
Focused ultrasound-mediated drug delivery to pancreatic cancer in a mouse model
Journal of Therapeutic Ultrasound, 2013
Background: Many aspects of the mechanisms involved in ultrasound-mediated therapy remain obscure. In particular, the relative roles of drug and ultrasound, the effect of the time of ultrasound application, and the effect of tissue heating are not yet clear. The current study was undertaken with the goal to clarify these aspects of the ultrasound-mediated drug delivery mechanism. Methods: Focused ultrasound-mediated drug delivery was performed under magnetic resonance imaging guidance (MRgFUS) in a pancreatic ductal adenocarcinoma (PDA) model grown subcutaneously in nu/nu mice. Paclitaxel (PTX) was used as a chemotherapeutic agent because it manifests high potency in the treatment of gemcitabine-resistant PDA. Poly(ethylene oxide)-co-poly(D,L-lactide) block copolymer stabilized perfluoro-15-crown-5-ether nanoemulsions were used as drug carriers. MRgFUS was applied at sub-ablative pressure levels in both continuous wave and pulsed modes, and only a fraction of the tumor was treated. Results: Positive treatment effects and even complete tumor resolution were achieved by treating the tumor with MRgFUS after injection of nanodroplet encapsulated drug. The MRgFUS treatment enhanced the action of the drug presumably through enhanced tumor perfusion and blood vessel and cell membrane permeability that increased the drug supply to tumor cells. The effect of the pulsed MRgFUS treatment with PTX-loaded nanodroplets was clearly smaller than that of continuous wave MRgFUS treatment, supposedly due to significantly lower temperature increase as measured with MR thermometry and decreased extravasation. The time of the MRgFUS application after drug injection also proved to be an important factor with the best results observed when ultrasound was applied at least 6 h after the injection of drug-loaded nanodroplets. Some collateral damage was observed with particular ultrasound protocols supposedly associated with enhanced inflammation.
Ultrasound in Medicine & Biology, 2010
Ultrasound sonication with microbubbles (MBs) was evaluated for enhancement of the release of nanoparticles from vasculature to tumor tissues. In this study, tumor-bearing Balb/c mice were insonicated with focused ultrasound (FUS) in the tumors after the injection of MBs (SonoVue Ò ) and then lipid-coated quantum dot (LQD) nanoparticles (130 ± 25 nm) were injected through the tail vein. We studied the effects of the injected MB dose (0-300 mL/kg), sonication duration (0-300 s) and treatment-procedure sequence on the accumulation of nanoparticles in the tumors 24 h after the treatment and the time response of the accumulation (0.5-24 h). After the treatment, the mice were sacrificed and perfused and then the tumor tissues were harvested for quantifying the amount of nanoparticles using graphite furnace atomic absorption spectrometry (GF-AAS). The results showed that pulsed-FUS sonication with MBs can effectively enhance the vascular permeability for LQD nanoparticle delivery into the sonicated tumors. It indicates that this technique is promising for a better nanodrug delivery for tumor chemotherapy. (
Ultrasonic-activated micellar drug delivery for cancer treatment
Journal of Pharmaceutical Sciences, 2009
The use of nanoparticles and ultrasound in medicine continues to evolve. Great strides have been made in the areas of producing micelles, nanoemulsions, and solid nanoparticles that can be used in drug delivery. An effective nanocarrier allows for the delivery of a high concentration of potent medications to targeted tissue while minimizing the side effect of the agent to the rest of the body. Polymeric micelles have been shown to encapsulate therapeutic agents and maintain their structural integrity at lower concentrations. Ultrasound is currently being used in drug delivery as well as diagnostics, and has many advantages that elevate its importance in drug delivery. The technique is noninvasive, thus no surgery is needed; the ultrasonic waves can be easily controlled by advanced electronic technology so that they can be focused on the desired target volume. Additionally, the physics of ultrasound are widely used and well understood; thus ultrasonic application can be tailored towards a particular drug delivery system. In this article, we review the recent progress made in research that utilizes both polymeric micelles and ultrasonic power in drug delivery. ß
Ultrasonic Nanotherapy of Pancreatic Cancer: Lessons from Ultrasound Imaging
Molecular Pharmaceutics, 2010
Pancreatic ductal adenocarcinoma (PDA) is the fourth most common cause of cancer death in the United States, with a median survival time of only 3-6 months for forty percent of patients. Current treatments are ineffective and new PDA therapies are urgently needed. In this context, ultrasoundmediated chemotherapy by polymeric micelles and/or nanoemulsion/microbubble encapsulated drugs may offer an innovative approach to PDA treatment. PDA xenografts were orthotopically grown in the pancreas tails of nu/nu mice by surgical insertion of Red Fluorescence Protein (RFP)transfected MiaPaCa-2 cells. Tumor growth was controlled by fluorescence imaging. Occasional sonographic measurements correlated well with the formal tumor tracking by red fluorescence. Tumor accumulation of paclitaxel-loaded nanoemulsion droplets and droplet-to-bubble transition under therapeutic ultrasound was monitored by diagnostic ultrasound imaging. MiaPaCa-2 tumors manifested resistance to treatment by Gemcitabine (GEM). This drug is the gold standard for PDA therapy. The GEM-resistant tumors proved sensitive to paclitaxel. Among six experimental groups studied, the strongest therapeutic effect was exerted by the following drug formulation: GEM + nanodroplet-encapsulated paclitaxel (nbGEN) combined with tumor-directed 1-MHz ultrasound that was applied for 30 s four to five hours after the systemic drug injection. Ultrasound-mediated PDA therapy by either micellar or nanoemulsion encapsulated paclitaxel resulted in substantial suppression of metastases and ascites suggesting ultrasound-enhanced killing of invasive cancerous cells. However, tumors relapsed after the completion of therapy, indicating survival of some tumor cells. The recurrent tumors manifested development of paclitaxel resistance. Ultrasound imaging suggested non-uniform distribution of nanodroplets in the tumor volume due to irregular vascularization, which may result in the development of zones with sub-therapeutic drug concentration. This is implicated as a possible cause of the resistance development, which may be pertinent to various modes of tumor nanotherapy.
Application of Ultrasound for Targeted Nanotherapy of Malignant Tumors
Acoustical physics, 2009
The article describes the study of targeted chemotherapeutic intervention on solid tumors by means of ultrasound and doxorubicin- or paclitaxel-loaded perfluoropentane nanoemulsions. Nanodroplets of the emulsions accumulated in a tumor by passive targeting. Under the action of a tumor-directed therapeutic ultrasound, the nanodroplets converted into vapor microbubbles. In vivo, the nanodroplets strongly retained the loaded drugs; yet, under ultrasound-mediated vaporization they released the drugs into the tumor tissue, thereby implementing effective targeting into the tumor. The tumors subjected to this treatment regressed effectively; however, after some time they recurred. The recurring tumors were more resistant to the repeated therapy than the primary ones. At present, the causes of of the resistance development and methods for its elimination are unclear and they are under investigation.